The long-range goal of this investigation is to determine the basis for naturally acquired immunological tolerance to self antigens. An understanding of self-tolerance is pertinent to tissue transplantation and autoimmune diseases, and is central to many questions that arise in connection with how the immune system carries out its natural host protective functions. The studies will concentrate on the minor H antigen defined by the H-24 locus of mice because, among presently known H antigens, it is especially well suited for self-tolerance studies. The proposed experiments have the following specific aims: 1. To determine the cellular immunological basis for natural tolerance of B6.C-H-24c/By mice to the H-24c-defined minor H antigen. It will be determined whether there are naturally occurring suppressor T cells that may be responsible for self-tolerance to the H-24c antigen. It will also be determined whether lymphocytes having the potential to react destructively against tissues and cells expressing the H-24c antigen are either functionally deleted in B6.C-H-24c mice, or are maintained instead in an actively suppressed state. Whether self-tolerance to the H-24c antigen occurs via an MHC-restricted mechanism will also be investigated. 2. To determine whether the thymus is a unique site for the induction of self-tolerance to H-24 and other minor H antigens. 3. To determine the pattern of expression of the H-24c antigen in various tissues and at various developmental stages in order to identify potential sites and times at which self-tolerance may take place naturally. 4. To determine whether a progressively growing tumor that expresses the H-24 antigen induces in its host a state of antigen- specific immunological unresponsiveness, and whether that unresponsiveness is essentially equivalent to self-tolerance. To address these aims, tissue-grafting experiments will be performed in which cells from mice that are naturally tolerant to the H-24 antigen will be transferred to other hosts, in order to reveal how the tolerant state is achieved and maintained.